Project Summary/Abstract Crohn's disease and Ulcerative Colitis, collectively referred to as inflammatory bowel disease (IBD) are devastating diseases that affect over one million people in the US. Current IBD therapies target the immune system, leaving patients susceptible to opportunistic infections. Therefore, the discovery of new therapeutics for IBD is an important priority. Recent studies have discovered several metabolites produced exclusively by gut bacteria that exert immunomodulatory effects at the mucosal interface. Indolepropionic acid (IPA) has emerged as the most exciting compound thus far in that it specifically engages host receptors and protects from experimental colitis in mice. This compound is produced by a discrete number of strictly anaerobic gut commensal bacteria including Clostridium sporogenes. Strategies to modulate levels of IPA could represent a new adjunct therapy for IBD patients. Despite the broad interest in this compound, the specific biochemical pathways involved in its synthesis are entirely unknown. Our long-term objective is to develop new therapeutic strategies aimed at controlling the metabolic output of gut bacterial communities. The goal of the current proposal is to unravel the biochemical pathway for IPA synthesis in C. sporogenes and to establish methods for increasing its production within the gut. The specific aims are to: 1) Determine how metabolic engineering and nutrient availability influence IPA production by Clostridium sporogenes in vitro, and 2) Develop strategies for ecosystem restructuring to promote therapeutic IPA production in the mouse gut. We will leverage newly developed genetic tools to understand how and why gut bacteria produce IPA. Using this information, we will assemble synthetic microbial communities in the gut designed to promote colonization by IPA producing bacteria. Finally, we will use these communities to reprogram IPA levels in mice and test whether we can protect against experimental colitis. The outcomes of these aims will represent the first steps toward controlling the metabolic output of gut bacteria for clinical benefit. This knowledge will be broadly relevant to modulating other microbial metabolites implicated in human diseases such as uremia, liver disease, cardiovascular disease, and autism. The proposed research is part of a mentored career development plan to achieve an academic career studying host-microbe interactions. The principal investigator is a PhD-trained microbiologist with training in Clinical Pathology. My goal as an independent scientist is to understand the microbial contribution to the biochemical inventory within our body. The mentor for this project is Dr. Justin Sonnenburg, a pioneer in studying the contribution of gut bacteria to host biology. The career development plan includes a research advisory board, a career development committee, seminars in microbial physiology, formal coursework in bacterial genetics and ecology, and presentations at microbiome and human metabolic conferences. These activities will provide the necessary environment and experiences for developing an independent research career.